Transcript Acid-Base_Handling

Renal Acid-Base Handling
Introduction
• [H+] is maintained within narrow limits
• Normal extracellular [H+] ≈ 40 nanomol/L
(one-millionth the mmol/L concentrations of
Na+, K+, Cl-, HCO3-)
• Regulation of [H+] at this low level is essential
for normal cellular (protein) fxn
– Increase in [H+] change charge, shape and
function of proteins
3 Basic Steps of H+ Regulation
• Chemical buffering by extracellular and
intracellular buffers
• Control of partial pressure of CO2 in the blood
by alterations in alveolar ventilation
• Control of plasma [HCO3-] by changes in renal
H+ excretion
Buffers
• Take up or release H+ ions to maintain a stable
[H+]
• HPO42- (base) + H+ ⇄ H2PO4- (acid)
• HCO3- (base) + H+ ⇄ H2CO3 (acid)
Henderson-Hasselbalch Equation
• Ka (dissociation constant) =
• [H+] = Ka
[H+] [A-]
[HA]
[HA]
[A-]
• -log [H+] = -log Ka - log [HA]
• pH = pKa + log [A-]
[A-]
[HA]
• pH = 6.10 + log [HCO3-]/0.03 Pco2
• H+ + HCO3- ⇄ H2CO3 ⇄ H20 + CO2
Bicarbonate Buffer System
• The major physiologic buffer system
• [HCO3-] and Pco2 regulated independently
– [HCO3-] regulated by renal H+ excretion
– Pco2 regulated by changes in alveolar ventilation
• As H+ are buffered by HCO3, elevation in Pco2 is
prevented by increase in alveolar ventilation, thus
enhancing effectiveness of HCO3 buffering
• Capable of removing large quantity of H+ due
to large amount of HCO3 in the body
Buffering During Metabolism of SulfurContaining Amino Acids
Diet
ECF
2H+
2 CO2 + 2 H2O
2 HCO3-
Sulfur-AA
SO42-
2 HCO3Glutamine
SO422 NH4+
2 NH4+
Kidney
Urine
•Acid balance is achieved when SO42- are excreted in the urine
with NH4+ because HCO3- is generated in the process
Buffering During Metabolism of
Organic Phosphates
Diet
ECF
H+
HCO3-
CO2 + H2O
RNA-PHCO3HPO42H2PO4-
Urine
CO2 + H2O
H+
Kidney
Base Balance During Metabolism of
Organic Anions
Diet
ECF
liver
HCO3-
H+
CO2
K+ + OA-
Glucose
OAK+
OAKidney
Urine
liver
Acid-Base Balance
Acid-Base
Balance
Production
H+
Removal H+
Acid
Balance
Base
Balance
Diet  2H+ + SO42-
Diet  3K+ + 3HCO3-
2H+ + HCO3-  2CO2 + 2H2O
Glucose  3H+ + Citrate3-
Add “new” HCO3-
2NH4 + SO4
2-
Removal
HCO3-
Excrete OA
Urine
+
Production
HCO3-
3K+ +
Citrate3-
Alveolar Ventilation
• Main physiologic stimuli to respiration
–  Pco2
• Chemoreceptors in respiratory center in brainstem
respond to CO2-induced ∆ cerebral interstitial pH
–  Po2
• Peripheral chemoreceptors in the carotid bodies
Sequential Response to H+ Load
Extracellular
buffering by
HCO3-
Intracellular and
bone buffering
Immediate
2-4 hours
Respiratory
buffering by
Pco2
renal H+
excretion
Minutes-Hours
Hours to Days
Renal H+ Excretion: Basic Principles
• Achieved by H+ secretion
– Na+/H+ exchange: proximal tubules and thick
ascending limb of the LOH
– H+-ATPase: collecting tubules
• Acid load cannot be excreted as free H+ ions
– Urinary [H+] is extremely low (< 0.05 mEq/L) in
the physiologic pH range
Renal H+ Excretion: Basic Principles
• Acid load cannot be excreted unless virtually
all of the filtered HCO3- has been reabsorbed
• Secreted H+ ions bind to:
– Filtered buffers (HPO42-, creatinine)
– NH3 to form NH4+
• Rate of NH4+ generation in the proximal tubules varies
according to physiologic needs
Renal H+ Excretion: Basic Principles
• Extracellular pH is the primary physiologic
regulator of net acid excretion
– Other factors include:
• Effective circulating volume
• Aldosterone
• Plasma [K+]
2 Basic Steps of Renal H+ Excretion
• Reabsorption of the filtered HCO3• Excretion of 50-100 mEq of H+ produced per
day (daily acid load on a typical Western diet)
Reabsorption of Filtered HCO3• Loss of filtered HCO3- = addition of H+
• Virtually all of the filtered HCO3- must be
reabsorbed
– Normal person reabsorbs about 4300 mEq of
HCO3- per day (GFR 180 L/day x 24mEq/L HCO3- )
Renal H+ Secretion
• Secreted H+ ions are generated within tubular
cells from dissociation of H2O
• OH- ions combine with CO2 to form HCO3-,
catalyzed by intracellular carbonic anhydrase
– HCO3- is absorbed across basolateral membrane
• Secretion of one H+ ion in the urine =
generation of one HCO3- in the plasma
Renal H+ Secretion
• If secreted H+ combines with filtered HCO3- ,
the result is HCO3- reabsorption thus
preventing HCO3- loss in the urine
• If secreted H+ combines with HPO42- or NH3, a
new HCO3- is added to the plasma (replaces
the HCO3- lost in buffering the daily H+ load)
Net Acid Excretion
Net Acid Excretion (NAE) = titratable acid + NH4+ - urinary HCO3-
quantity not
replenishable
(HPO42-, Cr)
excretion can be
increased
Titratable acid represents the amount of alkali that is required to titrate the
urine pH back to the plasma pH (7.4)
Proximal Acidification
• Proximal tubules reabsorb 90% of filtered
HCO3• Primary step is secretion of H+ by Na+-H+
exchanger in luminal membrane
– Energy indirectly provided by Na+/K+ ATPase in
basolateral membrane
• HCO3- returned to systemic circulation by
Na+/3 HCO3- cotransporter
• Carbonic anhydrase plays central role
Proximal Acidification
UpToDate, 2009
Distal Acidification
• H+ secretion in distal nephron occurs in type A
intercalated cells in the cortical collecting
tubule and in the cells of the medullary
colllecting tubule
• H+ secretion is mediated by active luminal
secretory pumps
– H+-ATPase
– H+/K+ ATPase
Distal Acidification
• H+ secretion by intercalated cells is indirectly
influenced by Na+ reabsorption in the adjacent
principal cells
– Na+ absorption makes the lumen relatively
electronegative, thus promoting H+ secretion
• HCO3- reabsorption across basolateral
membrane is mediated by Cl-/ HCO3- exchanger
Type A Intercalated Cell
UpToDate, 2009
Type B Intercalated Cell
UpToDate, 2009
Type A vs B Intercalated Cells
Ammonium Generation and Excretion
Glutamine
2-Oxoglutarate2- + 2 NH4+
Liver
2 NH4+  Urea
2HCO3- to body
2 NH4+ in
urine
2 HCO3-
Ammonium Generation and Excretion
Exogenous
Endogenous
Proteins
2HCO3-
Methionine + Glutamine
2H+ + SO422 CO2
+
2H2O
2NH4+
H+
NH4+
+
NH3
2HCO32NH4+ + SO42-
Ammonium Generation and Excretion
UpToDate, 2009
Medullary Ammonium Recycling
Fluid, Electrolyte and Acid-Base Physiology, 2010
Ammonium Generation and Excretion
Comprehensive Pediatric Nephrology, 2008
Regulation of Renal H+ Excretion
• Extracellular pH
• Effective circulating volume
– Renin-angiotensin-aldosterone system
– Chloride depletion
• Plasma potassium
Extracellular pH Is Major Regulator of
Renal H+ Excretion
• NAE varies inversely with extracellular pH
• Acidemia⇑prox and distal acidification
– Proximal tubule
•
•
•
•
⇑luminal Na+/H+ exchange
⇑luminal H+-ATPase activity
⇑Na+/3HCO3- activity in basolateral membrane
⇑NH4 production from glutamine
– Collecting tubule
• ⇑luminal H+-ATPase activity in intercalated cells
• Alkalemia⇓prox HCO3- reabsorption and ⇑HCO3secretion in CCD
Effective Circulating Volume
• Hypovolemia activates RAAS system, causing
HCO3- reabsorption
– Angiotensin II
• ⇑luminal Na+/H+ exchange in proximal tubule
• ⇑basolateral Na+/3HCO3- activity in proximal tubule
– Aldosterone
• ⇑luminal H+-ATPase activity in collecting tubule
• ⇑basolateral Cl-HCO3- activity in collecting tubule
• ⇑Na+ absorption in principal cells in cortical collecting
tubule, resulting in net H+ secretion
Effective Circulating Volume
• Hypochloremia commonly occurs in metabolic
alkalosis
– Low filtered [Cl-] increases H+ secretion
• Cl- is passively cosecreted with H+ secretion via H+ATPase to maintain electroneutrality thus ability to
secrete H+ is enhanced with low tubular fluid [Cl-]
• In setting of low tubular fluid [Cl-], Na+ reabsorption
must be accompanied by H+ or K+ secretion in CCD
Hypochloremia Decreases HCO3Secretion
Type B Intercalated Cell
• Energy for luminal Cl/HCO3- exchange is
provided by favorable
inward gradient for Cl• Low tubular [Cl-]
⇓gradient thus less HCO3secreted
UpToDate, 2009
Plasma K+ Influences Renal H+
Secretion
Hypokalemia
Cell
ECF
K+
Changes in K+ balance lead to
transcellular cation shifts that
affect intracellular [H+]
Hypokalemia leads to low
intracellular pH
H+
Na+
Intratubular Acidosis Increases H+
Excretion in Hypokalemia
• ⇑H+ secretion in proximal tubule
– ⇑luminal Na+/H+ exchange
– ⇑basolateral Na+/3HCO3- activity
• ⇑NH4 generation from glutamine in proximal
tubule
• ⇑H+ secretion in distal nephron
– ⇑luminal H+/K+ ATPase, resulting in H+ secretion
and K+ absorption
Renal Acification: Summary
Molecular and Genetic Basis of
Renal Disease, 2007
References
• Rose BD, Post TW: Clinical Physiology of AcidBase and Electrolyte Disorders. New York,
McGraw-Hill, 2001, pp 299-371.
• Bidani A, Tuazon DM, Heming TA: Regulation
of Whole Body Acid-Base Balance. In DuBose
TD, Hamm LL (eds): Acid-Base and Electrolyte
Disorders. Philadelphia, Saunders, 2002, pp 121.
References
• Alpern RJ, Hamm LL: Urinary Acidification. In
DuBose TD, Hamm LL (eds): Acid-Base and
Electrolyte Disorders. Philadelphia, Saunders,
2002, pp 23-40.
• Halperin ML, Goldstein MB, Kamel KS: Fluid,
Electrolyte and Acid-Base Physiology.
Saunders, 2010, pp 3-29.
References
• UpToDate, 2009
• Mount DB, Pollak MR: Molecular and Genetic
Basis of Renal Disease: A Companion to
Brenner and Rector’s The Kidney. Saunders,
2007.
• Geary D, Schaefer F: Comprehensive Pediatric
Nephrology. Mosby, 2008.
Distal Acidification
Comprehensive Pediatric Nephrology, 2008
Chronic Metabolic Acidosis and
Respiratory Compensation
Clinical state
Arterial pH
[HCO3-], mEq/L
Pco2, mmHg
Baseline
7.40
24
40
7.29
19
40
Acute
7.37
19
34
Chronic
7.29
16
34
Metabolic acidosis
No compensation
Compensation
Medullary Transfer of Ammonium
Fluid, Electrolyte and Acid-Base Physiology, 2010